Compliance monitoring module for a breath-actuated inhaler

ABSTRACT

A compliance monitoring module for a breath-actuated inhaler comprising: a miniature pressure sensor, a sensor port of said sensor being pneumatically coupled to a flow channel through which a user can inhale; a processor configured to: receive a signal originating from a dosing mechanism of the inhaler indicating that medication has been released; receive data from a sensing element of the sensor; and based on said signal from said dosing mechanism and said data from said sensing element, make a determination that inhalation of a breath containing medication through said flow channel complies with one or more predetermined requirements for successful dosing; and a transmitter configured to, responsive to said determination, issue a dosing report

This application claims priority to U.S. application Ser. No. 62/043,120entitled COMPLIANCE MONITORING MODULE FOR A BREATH-ACTUATED INHALERfiled on Aug. 28, 2014, the contents of which are incorporated fullyherein by reference.

The present disclosure generally relates to monitoring of patientcompliance to medicament administration via an inhaler. Moreparticularly, the disclosure relates to the use of a miniature pressuresensor for compliance monitoring in a breath-actuated inhaler.

Inhalers or puffers are used for delivering medication into the body viathe lungs. They can be used, for example, in the treatment of asthma andchronic obstructive pulmonary disease (COPD). Types of inhalers includemetered dose inhalers (MDIs), dry powder inhalers (DPIs) and nebulisers.

Modern breath controlled nebulisers generally fall into one of twocategories: breath enhanced or breath actuated. Breath enhancednebulisers use patient airflow to control the flow of drug-containingaerosol to the patient. Since aerosol is generated continuously in thesenebulisers, some is wasted to the environment. Breath actuatednebulisers use inhalation and/or exhalation detection to turn theaerosol generator on and off with patient breathing. This improvesefficiency compared to breath enhanced nebulisers, since little if anydrug is lost to the environment. Detection in breath actuated devices isusually by heat and/or pressure sensors.

A common problem faced in respiratory drug delivery, regardless of thedevice used, is how to monitor patient adherence and compliance.

Adherence deals with the patient following the prescription label, forexample taking the prescribed number of doses per day. If theprescription calls for two doses each day, and the patient is taking twodoses a day, they are considered 100% adherent. If the patient is onlytaking one dose a day, they are only 50% adherent. In the latter case,the patient is not getting the treatment prescribed by their doctor.

Compliance, on the other hand, relates to how the patient uses theirdrug delivery device. If used in the manner recommended for effectivetreatment, they are 100% compliant. If not used properly however, theyare less than 100% compliant. Use of a breath-actuated inhaler involvesinhaling in a particular way; for example the inhalation may need to belong enough and hard enough to entrain a full dose of medicament. Forsome patients, for example children and the elderly, meeting therequirements for full compliance may be difficult. However, failing toachieve 100% compliance can reduce the effectiveness of the prescribedmedicament. When a doctor prescribes a medication, the efficacy of thattreatment is totally dependent on the patient using their deviceproperly and the proper number of times each day. If they fail to do so,the patient is likely to experience no improvement in their condition.Absent any means of verifying patient adherence/compliance, yet facedwith a patient for whom no improvement can be seen, the doctor may haveno choice but to prescribe a stronger dose or even a strongermedication. In some cases, this may put the patient at risk. This couldbe avoided if the doctor had some way of confirming that the patient wasactually getting the medication prescribed.

The approach followed by some pharmaceutical companies has been to addintegral dose counters to their drug delivery products. For example, adose counter may be triggered by the press of an actuation button or theopening of a cap or cover. Some breath-actuated inhalers compriseadherence dose counters triggered by opening of an aerosol valve,indicating that the patient has inhaled hard enough to release a dose ofmedicament. While this provides patients and caregivers objectiveevidence that a device has been used, it still fails to provide any kindof compliance information. There is no means of determining whether theuser has inhaled the entire dose, or whether they have inhaled onlyenough to actuate the aerosol valve and then ceased inhalation orreduced the strength of their inhalation below a level at which drug canbe entrained into the airflow. As such, there is a need for a productthat provides not only adherence information, but compliance informationas well.

A spirometer is an apparatus for measuring the volume of air inspiredand expired by a patient's lungs. Spirometers measure ventilation, themovement of air into and out of the lungs. From the traces, known asspirograms, output by spirometers, it is possible to identify abnormal(obstructive or restrictive) ventilation patterns. Existing spirometersuse a variety of different measurement methods including pressuretransducers, ultrasonic and water gauge.

In order to monitor the flows associated with breathing, a pressuresensor is most convenient because pressure information can be used todetermine flow, which can then be used to determine volume.

Pressure sensors used for breath detection generally measure thepressure difference across a section of the airway through which apatient breathes. This is commonly done using two connections, by tubingor other suitable conduits, to connect the sensor to the airway. It isalso possible to use a single connection to the airway, with the otherport open to the atmosphere. A single port gauge type sensor can also beused if the pressure within the airway is measured both before and afterflow is applied, the difference in readings representing the desiredpressure drops across the air path resistance. However, the uncertaintyassociated with the first (no flow) reading is generally high.

Regardless of the pressure sensor type used, pressure sensors aregenerally connected to patient airways using flexible tubing. Adisadvantage of such systems is the possibility of sensor damage relatedto fluid contamination in the form of spilled drug or patient secretions(mucous, sputum, etc.). In order to isolate the pressure sensor fromsuch contaminants, manufacturers often locate the pressure sensor somedistance from the measurement site using elastomeric tubing. However,liquids may still condense within the tubing, creating an environmentfor bacterial growth in areas exposed to the patient but not generallyaccessible for cleaning.

Another problem with conventional pressure sensors is thermal drift; thephenomenon by which the pressure reading can change over time withchanges in local temperature. It is possible to compensate for suchdrift using additional circuitry, but this adds cost and volume andincreases power requirements. Such circuitry can be located within thepressure sensor itself, but considering that the sensor is generallysomewhat removed from the gas being measured, the temperature detectedmay not be representative of that gas. The temperature monitoringcircuitry could be located at the patient, but this adds additionalcomponents, plus cost and complexity.

Yet another problem with conventional pressure sensors is susceptibilityto high radio frequency (RF) exposure. This can be a real issue whenoperating in close proximity to a radio transmitter, such as a mobilephone. Other potential sources include wireless communications devices,such as Wi-Fi routers and cordless phones, and various other forms ofinformation technology (IT) equipment such as wirelessly networkedprinters. Another issue with some conventional pressure sensors ishysteresis, the reluctance of a pressure sensing material such as adiaphragm to return to its original form, shape or position after beingdeformed. This is observed as a difference in output when passingthrough the same pressure from different directions (either from aboveor below the target pressure). When dealing with very low pressurechanges, such an offset can be large enough to mask the signal beingmeasured.

There are described herein new means of compliance monitoring usingpressure sensing that avoids some or all of the problems describedabove.

According to a first aspect, there is provided a compliance monitoringmodule for a breath-actuated inhaler comprising: a miniature pressuresensor, a sensor port of said pressure sensor being configured to bepneumatically coupled to a flow channel through which a user can inhale;a processor configured to: receive a signal originating from a dosingmechanism of the inhaler indicating that medication has been released;receive data from a sensing element of the pressure sensor; and based onsaid signal from said dosing mechanism and said data from said sensingelement, make a determination that inhalation of a breath containingmedication through said flow channel complies with one or morepredetermined requirements for successful dosing: and a transmitterconfigured to, responsive to said determination, issue a dosing report.

The miniature pressure sensor could be a microelectromechanical system(MEMS) pressure sensor or a nanoelectromechanical system (NEMS) pressuresensor.

Said one or more predetermined requirements for successful dosing couldcomprise one or more of: flow rate exceeding a predetermined thresholdvalue; inhalation duration exceeding a predetermined threshold value;flow rate exceeding a predetermined threshold value for at least apredetermined threshold duration; total volume inhaled exceeding apredetermined threshold value; and peak inspired flow (PIF) exceeding apredetermined threshold value.

The module could be configured for use with an inhaler comprising meansfor user-actuated priming of the dosing mechanism, and means forbreath-actuated release of medicament.

Said signal originating from the dosing mechanism could be transmittedin response to user-actuated priming of the dosing mechanism.

Said transmitter could be wireless.

The pressure sensor could be a MEMS barometric pressure sensor. Thesensor could be a piezo-resistive or capacitive MEMS pressure sensor.

Any two or more of the pressure sensor, processor and transmitter couldbe comprised in a single integrated circuit or System on Chip (SoC).

The module could further comprise said flow channel, the pressure sensorbeing located inside the flow channel, the pressure sensor optionallybeing located in a recess in an internal wall of the flow channel.

The module could further comprise said flow channel, the pressure sensorbeing located external to the flow channel and said sensor port beingpneumatically coupled to the flow channel via an opening in a wall ofthe flow channel.

The module could further comprise a seal arranged to pneumaticallycouple the sensor port to said opening, at least a part of said sealoptionally being sandwiched between the pressure sensor and the wall, atleast a part of said seal optionally extending from an exterior surfaceof said wall to a surface on which the pressure sensor is mounted so asto encapsulate the pressure sensor in a pneumatic chamber adjacent thewall.

Said wall and said seal could be formed by a two-shot moulding process.The module could further comprise a thermally conductive gasketsandwiched between the pressure sensor and the wall, said thermallyconductive gasket optionally acting as the seal.

The module could further comprise an air-permeable, water-impermeablefilter separating said sensor port from said flow channel.

The pressure sensor could comprise a metal housing.

The module could be configured to be affixed to the part of a main bodyof the inhaler that is uppermost in use, following sterilisation of oneor more parts of said main body. Said processor could be comprised inthe pressure sensor.

The module could further comprise a data buffer configured to store datareceived from a sensing element of the pressure sensor. Said data buffercould optionally be comprised in the pressure sensor. Said data buffercould be configured to store data corresponding to oneinhalation/exhalation waveform. Said data buffer could be a first in,first out (FIFO) data buffer.

The module could further comprise an additional MEMS barometric pressuresensor configured for monitoring environmental barometric activity.

The transmitter could be comprised in a transceiver configured tocommunicate data from and/or to the pressure sensor. The transmittercould be wireless. Said wireless transmitter could be a Bluetooth™subsystem, optionally a Bluetooth™ Low Energy (BLE) integrated circuitor System on Chip (SoC).

The pressure sensor and/or the transmitter could be mounted on a printedcircuit board (PCB).

The module could further comprise a battery, optionally a coin cell,arranged to power the pressure sensor.

The pressure sensor could have a sensitivity of 20 Pascals or less.

The pressure sensor could comprise a sensing element. The processorcould be configured to poll said sensing element at a frequency ofgreater than or equal to 100 Hz.

The module could further comprise control means for switching on thepressure sensor and/or waking the pressure sensor from a low powerstate.

Said control means could be activated by motion of a yoke attached to amouthpiece cover such that opening of said mouthpiece cover causes saidyoke to move in such a way as to activate the control means.

Said control means could be a mechanical switch, an optical sensor, anaccelerometer or a Hall effect sensor.

The processor could be configured to respond to said control meansswitching on and/or waking up the pressure sensor by taking a tarereading from said sensing element and calibrating data received from thesensing element subsequently using said tare reading.

The processor could be configured to determine a dynamic zero from amoving average of measurements by the pressure sensor, and dynamicallycalibrate the pressure sensor according to said dynamic zero.

The processor could be configured to filter out electrical noiseinherent to the pressure sensor and/or environmental anomalies in datareceived from a sensing element of the pressure sensor.

The module could further comprise a temperature sensor, optionallyintegral with the pressure sensor. The processor, optionally comprisedin one of the pressure and temperature sensors, could be configured toapply temperature compensation determined from data received from asensing element of the temperature sensor to data received from asensing element of the pressure sensor.

The inhaler could further comprise a mouthpiece, said sensor port beingpneumatically coupled to a flow channel in pneumatic communication withsaid mouthpiece.

According to a second aspect there is provided a breath-actuated inhalercomprising the module of the first aspect.

According to a third aspect there is provided an inhaler accessorycomprising the module of the first aspect, configured to be connected toan inhaler such that said sensor port is pneumatically coupled to a flowchannel in pneumatic communication with a mouthpiece of said inhaler.

According to a fourth aspect there is provided a method for monitoringpatient compliance to medicament administration via a breath-actuatedinhaler comprising: receiving a signal originating from a dosingmechanism of the inhaler indicating that medication has been released; aminiature pressure sensor, a sensor port of said sensor beingpneumatically coupled to a flow channel through which a user can inhale,sensing a pressure change at said sensor port; receiving data from asensing element of the sensor; based on said signal from said dosingmechanism and said data from said sensing element, making adetermination that inhalation of a breath containing medication throughsaid flow channel complies with one or more predetermined requirementsfor successful dosing; and responsive to said determination,transmitting a dosing report.

The miniature pressure sensor could be a microelectromechanical system(MEMS) pressure sensor or a nanoelectromechanical system (NEMS) pressuresensor. The MEMS pressure sensor could be a MEMS barometric pressuresensor. The sensor could be a piezo-resistive or capacitive MEMSpressure sensor. Said one or more predetermined requirements forsuccessful dosing could comprise one or more of: flow rate exceeding apredetermined threshold value; inhalation duration exceeding apredetermined threshold value; flow rate exceeding a predeterminedthreshold value for at least a predetermined threshold duration; totalvolume inhaled exceeding a predetermined threshold value; and peakinspired flow (PIF) exceeding a predetermined threshold value.

The method could further comprise: monitoring environmental barometricactivity using an additional MEMS barometric pressure sensor; andcalibrating said sensor having the sensor port pneumatically coupled tosaid flow channel against said additional sensor. The method couldfurther comprise: switching on the sensor or waking the sensor from alow power state; in response to the sensor switching on or waking up,taking a tare reading from a sensing element of the sensor; andcalibrating data received from the sensing element subsequently usingsaid tare reading.

The method could further comprise: determining a dynamic zero from amoving average of measurements by the sensor; and dynamicallycalibrating the sensor according to said dynamic zero.

The method could further comprise applying temperature compensation todata received from a sensing element of the pressure sensor using datareceived from a sensing element of a temperature sensor.

The method could further comprise storing data received from a sensingelement of the sensor in a data buffer. Said data could correspond toone inhalation/exhalation waveform.

Said transmitting could be wireless. Said wireless transmitting coulduse a Bluetooth™ protocol, optionally the Bluetooth™ Low Energy (BLE)protocol.

The method could further comprise the processor polling a sensingelement of the sensor at a frequency of greater than or equal to 100 Hz.

The method could further comprise filtering out inherent electricalnoise and/or environmental anomalies in data received from a sensingelement of the sensor.

The method could further comprise determining the volume of air inspiredor expired by a user of the inhaler from data sensed by a sensingelement of the sensor.

According to a fifth aspect there is provided a computer program productcomprising instructions for execution by a computer processor to performthe method of the fourth aspect.

According to a sixth aspect, there is provided a compliance monitoringmodule substantially as herein described with reference to theaccompanying figures.

According to a seventh aspect, there is provided an inhalersubstantially as herein described with reference to the accompanyingfigures. According to an eighth aspect, there is provided an inhaleraccessory substantially as herein described with reference to theaccompanying figures.

According to a ninth aspect, there is provided a method substantially asherein described with reference to the accompanying figures.

According to a tenth aspect, there is provided a computer programproduct substantially as herein described with reference to theaccompanying figures.

Examples of the present invention will now be described with referenceto the accompanying drawings, in which:

FIGS. 1 to 5 illustrate example arrangements for a miniature pressuresensor for breath detection with respect to a flow channel;

FIG. 6 is a schematic of example sensor electronics;

FIGS. 7A, 7B; 8A, 8B, 8C; 9; 10A, 10B, 10C; 11; 12A, 12B, 12C; and 13A,13B, 13C illustrate example configurations of compliance modules ininhalers;

FIG. 14 is a flowchart illustrating an example compliance monitoringmethod;

FIG. 15 is a flowchart illustrating example user-device interactions;and

FIGS. 16A and 16B are graphs showing test data.

Elements shown in the Figures are not drawn to scale, but only toillustrate operation. Like elements are indicated by like referencenumerals.

In addition to the differential (two port) type pressure sensors and thesingle port gauge type sensors, with separate measurements made beforeand after use, discussed above, absolute or barometric pressure sensorsare available. Barometric pressure sensors are referenced to vacuum.They are sometimes referred to as altimeters since altitude can bededuced from barometric pressure readings. Sensors of this type have notgenerally been considered for use in breath detection because of theirextremely wide range (20 to 110 kPa) and low resolution. Considering howa typical breath profile may generate pressure changes of the order ofonly 0.2 kPa, this would require operating the sensor over an extremelynarrow portion of its operating range.

However, with miniaturisation, including the introduction of MEMS andNEMS technologies, much improved sensors are now available. A typicalMEMS barometric sensor is capable of operation from 20 kPa to 110 kPaand can detect flow rates of less than 30 Ipm (litres per minute) whenpneumatically coupled to a flow path having a known flow resistance.

Using a barometric sensor enables use of the barometric pressure as abaseline throughout the measurement cycle, thereby addressing theuncertainty of other single port approaches. Q

Also, having knowledge of the local barometric pressure can provide someinsight into patient lung function. It is suspected that changes inatmospheric pressure, such as those associated with approaching stormfronts, may have an effect on patient breathing, possibly even relatedto asthma and COPD events.

Barometric pressure sensors are already in stressed condition, having anintegral reference port sealed within the device under vacuum. Thismeans that they have low hysteresis in the region of interest.

Due to the extremely small size and mass of their sensing elements, MEMSsensors are capable of reacting to extremely small pressure changes.Some are capable of resolving pressure changes as low as 1 Pa.

MEMS pressure sensors can include all of the requisite analoguecircuitry within the sensor package. Temperature compensation and/ordigital interfaces can also be integrated with the pressure sensor.

For example, the Freescale MPL3115A2 MEMS barometer/altimeter chip(pressure sensor) is digital, using an I²C interface to communicatepressure information to a host micro-computer.

MEMS pressure sensors can be packaged in metal. This provides RFshielding and good thermal conductivity for temperature compensation.

MEMS pressure sensors are also low cost, exhibit low power consumptionand are very small. This makes them especially suitable for use inportable and/or disposable devices which may, for example, be powered bybatteries such as coin cells.

The small size of MEMS pressure sensors makes it easy to incorporatethem into existing designs of inhalers. It may be easier to incorporatethem in or close to a mouthpiece to more accurately measure the pressurechange caused by a patient's inhalation or exhalation.

A miniature barometric pressure sensor can be connected directly to thepatient airway using only a small hole to the air path which does notrequire tubing of any kind. This minimizes the possibility of moisturecondensation and potential bacterial growth associated with elastomerictubing. An internal seal, for example a gel seal, can be included toprotect the sensor element from contamination.

An example of this type of arrangement is shown in FIG. 1. A miniaturebarometric pressure sensor 110 is placed against the flow channel 120through which a patient breathes. Airflow is substantially axial asindicated by arrow 130. The sensor port 111 is sealed in line with anopening 121 in flow channel wall 122 by a pneumatic (airtight) seal 140.(Note that, so long as there is a pneumatic connection between thesensor port and the flow channel, the seal need not be completelyairtight.) Sensor port 111 optionally comprises a filter, for example anair-permeable, water-impermeable filter. The flow channel and the sealcould be formed by a two-shot moulding process. The pressure sensor 110can be mounted on a printed circuit board (PCB) 150 to provideconnection to power sources and other electronics.

Instead of positioning the seal 140 around the channel between opening121 and sensor port 111, the entire miniature pressure sensor could beencapsulated within a chamber adjacent to the flow channel asillustrated in FIG. 2. Pneumatic seal 240 is located outside of thesensor footprint and extends all the way from the exterior of flowchannel wall 222 to the surface 250 on which the sensor 210 is mounted(for example the component surface of a PCB). FIG. 2 shows across-section; pneumatic seal 240 surrounds the perimeter of the sensor210 whether it is circular, square, rectangular or any other shape. Theseal 240, sensor mount 250 and flow channel wall 222 thus form a cavitypneumatically isolated from the external environment except for the flowchannel in the location of the opening 221. The pressure at the sensorport 211 is therefore equalised with the pressure in the flow channel atthe opening 221.

Since MEMS sensors are available with built-in temperature compensation,there may not be any need for use of external thermal sensors.Compensation can be provided right at the measurement site, increasingthe accuracy of the compensation. A MEMS sensor with built-intemperature compensation can also act as a compact breath thermometer,providing further information to the patient and/or their caregiver. Ifthe housing of the sensor is metal, then not only is the sensitiveinternal circuitry isolated from RF fields, such as those associatedwith mobile phones or nearby disturbances, but the sensor will alsorapidly equilibrate to the local temperature in order to provide optimumtemperature compensation.

In the embodiments of FIGS. 1 and 2, the miniature sensor is separatedfrom the flow channel wall by an air gap. To improve the ability of theminiature sensor to rapidly detect changes in flow channel temperature,a thermally conductive gasket can be used as shown in FIG. 3. (FIG. 3 isin other respects similar to FIG. 2.)

In the example arrangement of FIG. 3, a thermally conductive gasket 360,such as the silicone types used for transistor heat sinks, is providedbetween the (optionally metal) housing of the miniature sensor 310 andthe flow channel wall 322. The greater the adjacent surface areascovered by the gasket the quicker the temperature equilibration. Thegasket 360 could therefore extend over substantially the entire surfaceof the sensor 310 facing the flow channel wall 322.

FIG. 4 shows an example arrangement in which a thermally conductivegasket 460 is made of an air-impermeable substance which deforms to thecontours of the surfaces of the sensor 410 and flow channel wall 422 itis compressed between. It thus provides a good thermal connection whileat the same time acting as a pneumatic seal, eliminating the need for aseparate sealing element.

An alternative to positioning the sensor adjacent the flow channel is toplace the entire sensor within the low pressure airway of the device tobe monitored as illustrated in FIG. 5. For example, the sensor could beplaced within the body of a DPI or the ‘boot’ of a pressurised MDI(pMDI). (The term boot refers to the body of the inhaler that generallyholds the drug canister.) In this arrangement the sensor is trulymeasuring the pressure (and optionally, temperature) of the airflowitself, providing improved accuracy. Therefore there is also no need forany sealing element to create a pneumatic conduit between the flowchannel 520 and the sensor port 511, or for any thermally conductivegasket to aid in temperature equilibration between them. It is also notnecessary to provide the sensor with any access to the external pressureenvironment for reference purposes because the reference is alreadybuilt into the sensor itself in the form of a vacuum reference.

In the example of FIG. 5, the miniature barometric pressure sensor 510is mounted on the interior of flow channel wall 522, optionally via aPCB 550. The flow channel wall 522 may comprise a recessed part 523 inwhich the sensor 510 is located as shown to reduce disruption to theairflow indicated at 530. For example, the depth of such a recess 523could be substantially equal to the thickness of the sensor 510 so thatthe surface of the sensor comprising the sensor port 511 lies flush withthe parts of the interior surface of flow channel wall 522 to eitherside of the sensor 510. Recess 523 could be a volume cut out of the wall522 or a part of the wall that extends radially outwards relative to therest as shown.

It should be noted that due to their small size, MEMS pressure sensorscan be used to monitor patient flow through, for example, nebulisers,DPIs or pMDIs, thus facilitating low cost compliance monitoring, inaddition to/in place of adherence monitoring, which confirms deviceactuation. Said compliance monitoring could be implemented using anaccessory device that couples to the dosing device through a small holeto the airway to be monitored, or in the dosing device itself. The smallsize, high performance and low cost of MEMS sensors make them ideallysuited to such applications where size and weight are majorconsiderations for users who may have to carry their inhaler with themat all times.

If output from the miniature pressure sensor is digital, all low levelsignal processing can be done within the sensor, shielding it fromoutside interference. This makes it possible to work with signals of theorder of tens of Pascals without much difficulty, something thattraditional sensors with external circuitry would be challenged to do.FIG. 6 shows schematically some electronic components of an exampleminiature barometric pressure sensor. Sensor element 601 passes analoguesignals to analogue to digital converter (ADC) 602. The digital outputsignal of ADC 602 is then averaged by a rolling average filter over manycycles to reduce noise. Various averages can be selected under programcontrol in order to balance noise against response time.

As one example, block 603 represents a means of selecting one of eightdifferent oversample (i.e. filter) ratios to output at 604. The fastestresponse is associated with OSR=1, but this is also the noisiestsetting. Conversely, OSR=128 introduces the least noise, but has theslowest response. The optimum setting can be chosen depending on theparticular application. With an OSR setting of 16, the output is cleanenough and the update time quick enough for most respiratoryapplications.

It may be desired, for example in order to record patient flow profiles,to create a waveform associated with the real time fluctuations ofpressure detected by the sensor. If one were to construct such awaveform from single readings of the sensor each time new data becameavailable, the resulting waveform would exhibit blocky artefacts, ratherthan a smooth waveform, due to the delays associated with each tap.However, by driving the ADC 602 at a suitable frequency, for exampleapproximately 100 Hz, and reading data at the same rate, the datapresented to each tap is further averaged, resulting in a much smootherwaveform.

The averaged output can then be passed to a circular first in, first out(FIFO) buffer (not shown) for storage until the data can be processed bya connected processor integrated into the device, or transmitted foroffloaded processing. Such a FIFO buffer could, for example, store anumber of samples approximately equivalent to, or a little greater than,one typical breath waveform to ensure that an entireinhalation/exhalation profile can be captured. Using a buffer reducesthe demand on the serial port of the sensor in cases where the waveformis not required in real time. With the addition of communications it ispossible to monitor patient adherence and compliance and communicatesuch information, for example including patient flow profiles, to a userdevice such as a smart phone or tablet. From a user device data canoptionally be communicated to a caregiver's device, for example adoctor's personal computer (PC). This could be done using a wiredconnection, for example via a Universal Serial Bus (USB) port.Alternatively, using wireless technology, it is possible to communicateresults to the outside world without interrupting the product housing inany significant way. Suitable wireless technologies could include, forexample, WiFi technologies such as IEEE 802.11, Medical Body AreaNetwork (MBAN) technologies such as IEEE 802.15, Near FieldCommunication (NFC) technologies, mobile technologies such as 3G andBluetooth™ technologies such as Bluetooth™ Low Energy (BLE). A wirelesstransceiver, for example in the form of a BLE chip, could be connectedto the miniature sensor or integrated with it.

Such wireless connectivity could be used, for example, to report deviceactuation and/or sensed inhalation with date and time stamps in realtime. This data could be processed externally and if the result of suchprocessing is that it is determined that a prescription should berefilled, an alert can be sent to the patient and/or caregiver and/orpharmacist. Alerts could be provided via one or more user interfaces ofthe inhaler (for example an LED and/or a buzzer) or via text message oremail. As another example, if no dosing report is received within apredetermined period following a scheduled dosing time, a reminder couldbe sent to the patient and/or caregiver. Alerts could also be generatedfor example if use frequency is exceeding a safe threshold. Thecompliance module could communicate directly or indirectly with one ormore of: a user device (such as a mobile phone e.g. a smartphone, atablet, a laptop or a desktop computer) of a patient, or of a caregiver(such as a doctor, nurse, pharmacist, family member or carer), a servere.g. of a health service provider or inhaler or drug manufacturer ordistributor or a cloud storage system. Such communication could be via anetwork such as the Internet and may involve a dedicated app, forexample on the patient's smartphone.

Compliance monitoring means (such as one or more sensors, e.g. a deviceactuation sensor such as a mechanical switch to detect adherence andcompliance reporting means, e.g. a miniature pressure sensor to detectsufficient flow for proper dose delivery) and compliance reporting means(such as a wireless transmitter or wired output port) could be includedin a single module. This module could be sold as a separate inhaleraccessory/upgrade for attachment to an existing or slightly modifieddesign of inhaler. Alternatively, the compliance monitoring module couldbe incorporated into the inhaler during manufacture. It is not requiredfor all components of the compliance monitoring module to be comprisedin a single physical unit, though this may be the case. In the case ofan inhaler accessory version, the module could consist of one or moreattachable units. In the case of a module incorporated into an inhaler,the individual components could be located in any suitable locations inor on the inhaler and need not be grouped together or connected anyfurther than required for them to function.

The sensor could, for example, be used in the types of breath actuateddry powder inhalers described in PCT patent application publicationsnumbers WO 01/97889, WO 02/00281, WO 2005/034833 or WO 2011/054527.These inhalers are configured such that inhalation by the user throughthe mouthpiece results in an airflow through the device entraining drypowder medicament. The inhalation also results in another airflowentering the inhaler from outside. The inhaler comprises a swirl chamberin which the two airflows collide with one another and the chamber wallsto break down aggregates of the dry powder medicament for more effectivedelivery.

These inhalers comprise a dose counting mechanism for determining that abolus of powder has been metered from a hopper into a dosing chamberfollowing priming by a user. The dose metering system includes a pawlmovable along a predetermined path during the metering of a dose ofmedicament to the mouthpiece by the dose metering system. The dosecounter includes a bobbin, a rotatable spool, and a rolled ribbonreceived on the bobbin, rotatable about an axis of the bobbin. Theribbon has indicia thereon successively extending between a first end ofthe ribbon secured to the spool and a second end of the ribbonpositioned on the bobbin. The dose counter also includes teeth extendingradially outwardly from the spool into the predetermined path of thepawl so that the spool is rotated by the pawl and the ribbon advancesonto the spool during the metering of a dose to the mouthpiece.

However, these inhalers do not comprise any means of determining whetherthe dose has been successfully administered. The addition of a miniaturebarometric pressure sensor anywhere in the airflow path through theinhaler or anywhere in fluid communication with the airflow path couldenable compliance monitoring since such a miniature sensor could collectsufficient data to indicate whether or not the patient inhaled in anappropriate manner (e.g. hard enough and for long enough) to receive afull dose of medicament.

This information, combined with a signal originating from the dosemetering system indicating that a bolus of medicament was made availableto the flow channel through which the patient inhales prior to theinhalation, is sufficient to confirm that a dose has been successfullyadministered.

A signal could be obtained from the dose metering system in anyconvenient manner. For example, an electronic switch could be arrangedsuch that it is actuated by motion of the pawl or rotation of the spool.This switch could be connected to an input of the processor such thatthe processor receives an electronic pulse when a dose is metered. FIGS.7A, 7B; 8A, 8B, 8C; and 9 illustrate further details of how a compliancemodule could be integrated into such an inhaler.

FIGS. 7A, 7B illustrate examples in which a PCB 750 carrying a MEMSpressure sensor and optionally a processor and transmitter isincorporated into an inhaler 700 body close to a mouthpiece 770. In FIG.7A mouthpiece 770 is hidden by a cover 780. In FIG. 7B the cover 780 ispulled down to expose mouthpiece 770. Cover 780 is connected to a yoke790 such that when cover 780 is swung down to expose mouthpiece 770,yoke 790 is pulled down to close a tactile switch 795. When switch 795is closed, an electrical connection is formed between PCB 750 and abattery 755, such as a coin cell, so that the PCB 750 is only poweredwhen the mouthpiece cover 780 is open. This helps to conserve batterypower for when it is needed. Alternatively, the PCB 750 could always beconnected to the battery 755, but closing of switch 795 (or activationof some other switching means, e.g. an optical sensor, an accelerometeror a Hall effect sensor) could wake PCB 750 from a power-conservingsleep mode.

An alternative arrangement is shown in FIG. 8A. Similarly to the exampleshown in FIG. 7B, a mouthpiece 870 is exposed by swinging down a cover880 which results in the pulling down of a yoke 890. In this examplehowever, the PCB 850 (again carrying a MEMS pressure sensor andoptionally a processor and transmitter) is incorporated into a medianportion of the inhaler 800 body. The yoke 890 is formed in an “n” shapeto the left and right and above the PCB when the inhaler 800 is orientedfor use (with the mouthpiece horizontal at the downward end). FIG. 8Bshows an enlarged view of the PCB and yoke when the cover is closed.FIG. 8C shows a similar view when the cover is opened. In FIG. 8C, thehorizontal part of the yoke 890 is pulled down to close a tactile switch895. Similarly to the example of FIG. 7B, when switch 895 is closed, anelectrical connection is formed between PCB 850 and a battery 855, suchas a coin cell, so that the PCB 850 is only powered when the mouthpiececover 880 is open. Alternatively, the PCB 850 could always be connectedto the battery 855, but closing of switch 895 (or activation of someother switching means, e.g. an optical sensor, an accelerometer or aHall effect sensor) could wake PCB 850 from a power-conserving sleepmode.

A further alternative arrangement is shown in partially exploded form inFIG. 9. Similarly to the examples shown in FIGS. 7B and 8A, a mouthpiece970 is exposed by swinging down a cover 980 which results in the pullingdown of a yoke 990. In this example however, the PCB 950 (again carryinga MEMS pressure sensor and optionally a processor and transmitter) isincorporated into the top of the inhaler 900 body. A collar 997 aroundthe PCB 950 is clipped onto the top of the yoke (not shown) towards theend of manufacture of the inhaler 900. This can be done followingsterilisation of parts of the inhaler body. This is advantageous sincethe sterilisation process could damage the sensitive electronics on thePCB 950. In this example the yoke 990 is configured to rise when themouthpiece cover 980 is opened. This pushes the horizontal top part ofthe yoke 990 (which is similar to that shown in FIG. 8B) up to closetactile switch 995. Similarly to the examples of FIGS. 7A, 7B, and 8C,when switch 995 is closed, an electrical connection is formed betweenPCB 950 and a battery 955, such as a coin cell, so that the PCB 950 isonly powered when the mouthpiece cover 980 is open. Alternatively, thePCB 950 could always be connected to the battery 955, but closing ofswitch 995 (or activation of some other switching means, e.g. an opticalsensor, an accelerometer or a Hall effect sensor) could wake PCB 950from a power-conserving sleep mode.

Indicator light emitting diodes (LEDs) visible through (optionallycoloured) windows or light pipes 952 shown on the exterior of theinhaler 900, preferably in a position visible to a user during dosing,are also powered by battery 955 and can be controlled by a processor onthe PCB. LEDs 952 can be used to provide information to a user and/orcaregiver by indicating, for example with different colour and flashcombinations, that e.g. the mouthpiece cover is open (and therefore theinhaler is primed for dosing) and/or it is time to refill a prescriptionand/or that (according to processing of the pressure sensor readings)dosing is complete/has not been fully completed.

Another alternative arrangement is shown in FIGS. 10A, 10B, 10C. In thiscase yoke 1090, linked to a hinged mouthpiece cap (not shown) carriesbellows 1091, made of a partially compliant material.

FIG. 10A shows the bellows position when the cap is closed. A foot of aspring arm 1092 is received in a recess 1093 in the upper wall of thebellows. The bottom of the recess 1093 therefore pushes on the lowersurface of the foot such the spring arm is biased upwards. This causes ahead of the spring arm 1092 to close a switch 1095 which keeps PCB 1050in sleep mode.

FIG. 10A shows the arrangement as opening of the cap is begun, when yoke1090 and therefore bellows 1091 move slightly upwards. Spring arm 1092remains contacting the switch 1095 and the compliance of the bellowsmaterial relieves any additional strain which would otherwise be put onthe switch since the bottom of recess 1093 bends to take the strain.

FIG. 10C shows the arrangement when the cap is fully open. The yoke 1090and bellows 1091 have moved down clear of the spring arm 1092, whichrelaxes down away from switch 1095. Switch 1095 is therefore opened,waking the PCB 1050.

Optionally, a grub screw may be included to fine tune the contactbetween the switch and spring arm.

As another example, the sensor could be used in the types of breathactuated pressurised aerosol inhalers described in PCT patentapplication publication numbers WO 01/93933 or WO 92/09323. Theseinhalers comprise a means for releasing a measured dose of medicament,the releasing means comprising a means for priming the device byapplying a preload capable of actuating delivery means, a means forapplying a resisting pneumatic force capable of preventing actuation ofthe delivery means and a release device capable of freeing the resistingpneumatic force to allow the preload to actuate the delivery means anddispense the medicament. The pneumatic resisting force can beestablished by mechanisms comprising, for example, a diaphragm, a pistoncylinder, a bellows or a spring. Inhalation through a valve or past avane mechanism allows the preload to actuate an aerosol valve to releasemedicament. While adherence could be monitored for such inhalers bydetermining when the device is primed and/or when the aerosol valveopens, they do not comprise any means of determining whether the userhas inhaled the entire dose. Again, the introduction of a MEMSbarometric pressure sensor anywhere in the airflow path through theinhaler or anywhere in fluid communication with the airflow path, incombination with means for determining when the device has been primedand/or when the aerosol valve opens, could enable compliance monitoring.

Priming the device could result in both a preload being applied to thedelivery means and a load being applied to an electronic switch. Thisswitch could be connected to an input of the processor such that theprocessor receives an electronic pulse when the device is primed.Alternatively or additionally, an electronic switch could be arranged tobe actuated by motion of the aerosol valve or of the valve or vanemechanism preceding the aerosol valve. This switch could be connected toan input of the processor such that the processor receives an electronicpulse when aerosol is released to the flow channel through which thepatient inhales. The switch could be, for example, mechanical, optical,proximity-based or an accelerometer.

FIGS. 11; 12A, 12B, 12C; and 13 illustrate how a compliance module couldbe integrated into such an inhaler.

FIG. 11 shows a compliance module 1150 located at the base of an inhaler1100. FIGS. 12A, 12B and 12C show a compliance module 1250 located atthe top, median portion and bottom respectively of the back of aninhaler 1200.

The compliance modules of FIGS. 11 and 12A, 12B, and 12C could be addedduring manufacture of the inhalers, or could be optional accessorieswhich can be clipped onto the inhalers later. That is, the module couldbe connected (optionally reversibly) to the inhaler via fastening meansand be in fluid communication with the inhaler interior and hence theairflow path via one or more apertures in the inhaler body.

FIGS. 13A, 13B, and 13C illustrate how a compliance module 1350 could beincorporated into the top of an inhaler. FIG. 13A shows the defaultposition of a retainer ring 1390, pushing up onto a tactile switch 1395to open it. With the switch 1395 open, there is no electrical connectionbetween the compliance module 1350 and a battery 1355 such as a coincell. FIG. 13B shows the position of retainer ring 1390 when the inhaleris primed for use, lowered with respect to the switch 1395 to close itso that compliance module 1350 is powered. FIG. 13C illustrates thefinal stages of manufacture of the inhaler shown in FIGS. 13A and B. Thecompliance module 1350 is lowered onto the inhaler body then a cap 1398is clipped in place. As with the example of FIG. 9, LED indicators 1352can be provided.

It should be noted that because MEMS barometric pressure sensors respondto environmental barometric pressure, which can change over time,attention should be paid to the initial reading that any subsequentsensor output signal analysis is based upon. An automatic zero reading(i.e. tare) could be performed immediately prior to monitoring anyinhalation signal. While it is possible for this value to change overtime in response to changes in local environmental barometric pressure,it would not be expected to cause any issues if a treatment is completedwithin a few minutes. Alternatively, a second barometer chip could beused to keep track of barometric activity, allowing the primary chip tobe used exclusively for breath detection.

The point at which dosing is complete (i.e. where lung volume peaks)could correspond to the point at which flow reverses direction. Thus,the processor can make a determination that dosing is complete when thedata from the pressure sensor indicates that flow direction hasreversed.

Not all processing needs to be done by the module. Any or all processingcould be offloaded to an external data processing device. A wirelessscheme (for example comprising a BLE module) could be used to transmitpatient flow profiles to an app which could then calculate specificbreathing parameters. The inhaler could thereby offload the processingrequired for such a task to, for example, a smart phone processor. Thiswould facilitate the smallest form factors possible for the inhalers. Afurther advantage of this approach is that software running on a smartphone can be changed more readily than software running on an inhaler.

FIG. 14 is a flowchart illustrating an example compliance monitoringmethod. At step 1410 a user primes their inhaler for use, for example bypressing a button or opening a mouthpiece cover. At 1420 the user startsto inhale through a mouthpiece of the inhaler. At 1430 the processor ofthe compliance module receives a dose release signal. This signal mayhave been transmitted by the dosing mechanism either in response topriming of the inhaler at 1410 or in response to a pressure sensor orother mechanism sensing that inhalation has begun. For example,inhalation may cause opening of a valve which results in both release ofmedicament into the flow channel through which the user is inhaling andactuation of an electrical switch to trigger a dose release signal. At1440 the MEMS pressure sensor detects a pressure change in the flowchannel. At 1450 the processor receives data from the sensor. At 1460the processor determines from the sensor data that one or morepredetermined requirements for successful dosing have been met. Forexample, the sensor data could indicate that flow rate in the flowchannel in the inhalation direction exceeded a predetermined thresholdvalue for at least a predetermined threshold duration. Alternatively,the sensor data could be processed such that flow rate is integratedover the time period that the sensor detected inhalation to determinetotal inhaled volume, and this volume could be compared to apredetermined minimum volume for successful dosing. At 1470 a dosingreport is transmitted in response to the processor's determination, forexample by a wireless transmitter or via a wired output.

FIG. 15 is flow chart illustrating example control logic for indicatingbreath actuated inhaler compliance data to both a user and an externalentity. The example inhaler is equipped with an indicator LED, a buzzerand a wireless transmitter. It also has a cap linked to a dosingmechanism such that opening the cap primes the inhaler by making a bolusof medicament available to a flow channel through which the user canthen inhale. To make the next dose available, the cap must be closed andthen opened again. A MEMS pressure sensor is arranged to senseinhalation through the flow channel and a further sensor (e.g. a switch)is arranged to detect opening and closing of the cap.

At 1510 the inhaler is in sleep mode. Opening of the cap at 1520 wakesthe inhaler and switches on an LED at 1530. If compliant inhalation(i.e. inhalation meeting whatever criteria are required to confirmdosing is complete) is detected at 1540, at 1550 the LED is switched offand the buzzer issues a brief confirmation beep. If the cap is thenclosed at 1560, at 1590 compliance data indicating that a dose has beensuccessfully taken and the device shut down correctly is transmitted,e.g. to a device of the user or a caregiver. The inhaler then returns tosleep mode.

If at 1560 the cap is not closed, the device enters a timeout loop at1561. If timeout occurs, at 1562 a long error beep is issued. Compliancedata indicating that a dose has been taken but the device has been leftopen, and therefore is not ready for subsequent dosing, is thentransmitted at 1590 before the inhaler re-enters sleep mode. If thedevice is a rescue inhaler, for example to be used during an asthmaattack, this type of compliance data could indicate that the medicationhas been successfully taken but has not enabled the user to recover. Anautomated system could therefore be in place to call paramedics to theuser's location (which could for example be known thanks to a GPStracker in the inhaler or a user device such as a smartphone or tabletin communication with the inhaler).

If compliant inhalation is not detected at 1540, at 1570 it isdetermined whether the cap has been closed. If not, a timeout loop isentered at 1571 which cycles through 1540, 1570, 1571. If timeout occursat 1571, at 1572 a long error beep is issued by the buzzer. Compliancedata is then transmitted at 1590, indicating that a dose has been loadedbut not successfully taken. The inhaler then returns to sleep mode.Again, if the inhaler is a rescue inhaler, transmission of this kind ofcompliance data could trigger calling of paramedics.

If the cap is closed at 1570, then at 1580 the LED is switched off andat 1590 compliance data is transmitted indicating that a dose has beenloaded in error. The inhaler then re-enters sleep mode.

The inhaler may further be capable of determining when inhalation isattempted again following a compliant inhalation without a new dosefirst being loaded (i.e. without the cap being closed and opened). Thiscould trigger an error beep.

FIGS. 16A and 16B show the mean pressures measured using a miniaturerelative pressure sensor affixed to the upper part of the casing of 10different inhalers versus a series of air flow rates applied through thedevice. Repeat measurements were included for start, middle and end oflife of each inhaler (in terms of progress through the number of “shots”before the doses run out). In FIG. 16A, error bars are shown for a +/−3sigma variation. In FIG. 16B, error bars are shown for a +/−2 sigmavariation, capturing a band that 95% of inhalers would fall into. We canthus get an idea of flow uncertainty for pressure measurements by such asensor used in an inhaler.

For typical inhalation flow rates (30-60 l/min), the uncertainty can becalculated from FIG. 16A as ˜16 l/min. (The uncertainty in flow rate foreach measurement can be estimated as the flow axis differential betweenthe top of the error bar for the measurement and the point at which aline joining the bottoms of the error bars for that measurement and thenext reaches the measured pressure. So, for the 30 l/min measurement,the differential is ˜41 l/min minus 30 l/min=11 l/min. For 45 l/min thedifferential is 15 I/min and for 60 l/min it is 22 l/min.) Theequivalent value taken from FIG. 16B is ˜10 l/min. Sufficient precisioncan thus be obtained to provide useful compliance data.

The above description relates to exemplary uses of the invention, but itwill be appreciated that other implementations and variations arepossible.

In addition, the skilled person can modify or alter the particulargeometry and arrangement of the particular features of the apparatus.Other variations and modifications will also be apparent to the skilledperson. Such variations and modifications can involve equivalent andother features which are already known and which can be used instead of,or in addition to, features described herein. Features that aredescribed in the context of separate embodiments can be provided incombination in a single embodiment. Conversely, features which aredescribed in the context of a single embodiment can also be providedseparately or in any suitable sub-combination.

1-20. (canceled)
 21. A breath-actuated inhaler comprising: a medicament;a mouthpiece; a cover; and a monitoring module comprising a sensor, awireless transmitter, and a processor, the monitoring module configuredto change from a first power state to a second power state when thecover is moved to expose the mouthpiece, wherein the second power stateis characterized by a power consumption that is greater than the firstpower state.
 22. The breath-actuated inhaler of claim 21, wherein thesensor comprises a pressure sensor.
 23. The breath-actuated inhaler ofclaim 22, wherein the pressure sensor comprises a microelectromechanicalsystem (MEMS) pressure sensor or a nanoelectromechanical system (NEMS)pressure sensor.
 24. The breath-actuated inhaler of claim 21, wherein adose of the medicament is configured to be primed for a user when thecover is moved to expose the mouthpiece.
 25. The breath-actuated inhalerof claim 21, wherein the first power state is an off state or a sleepstate, and the second power state is an on state.
 26. Thebreath-actuated inhaler of claim 21, further comprising: a yokeconnected to the cover, wherein the yoke is configured to activate aswitch when the cover is moved to expose the mouthpiece, and theactivation of the switch changes the monitoring module from the firstpower state to the second power state.
 27. The breath-actuated inhalerof claim 21, further comprising: a bellows, a spring, and a switch,wherein, when the cover is moved to expose the mouthpiece, the bellowsand the spring are configured to move in a direction away from theswitch, which actuates the switch and changes the monitoring module fromthe first power state to the second power state.
 28. The breath-actuatedinhaler of claim 21, wherein, when the cover is moved to expose themouthpiece, the processor is configured to provide a primed indicationto a user, the primed indication indicating that the breath-actuatedinhaler is primed for use by the user.
 29. The breath-actuated inhalerof claim 21, wherein the wireless transmitter comprises at least one ofa Bluetooth Low Energy (BLE) integrated circuit or a BLE system on chip(SoC).
 30. The breath-actuated inhaler of claim 21, wherein theprocessor is configured to generate a time stamp when the monitoringmodule changes from the first power state to the second power state. 31.The breath-actuated inhaler of claim 30, wherein the wirelesstransmitter is configured to transmit the time stamp to a user device,the user device comprising a smartphone, a tablet, a laptop, or adesktop computer.
 32. The breath-actuated inhaler of claim 21, whereinthe wireless transmitter is configured to transmit a dosing report to auser device, the user device comprising a smartphone, a tablet, alaptop, or a desktop computer.
 33. The breath-actuated inhaler of claim21, wherein the wireless transmitter is configured to transmit at leastone of an inhalation time or an inhalation duration to a user device,the user device comprising a smartphone, a tablet, a laptop, or adesktop computer.
 34. The breath-actuated inhaler of claim 21, furthercomprising a light emitting diode (LED), wherein the processor isconfigured to change a color of the LED or flash the LED upon themonitoring module changing from the first power state to the secondpower state.
 35. The breath-actuated inhaler of claim 21, wherein thesensor is positioned distal to the mouthpiece.
 36. The breath-actuatedinhaler of claim 21, wherein the monitoring module is adapted todetermine a pressure reading in the mouthpiece using the sensor.
 37. Amonitoring module for an inhaler, the monitoring module comprising: awireless transmitter; a sensor; and a processor in communication withthe wireless transmitter and the sensor, the monitoring moduleconfigured to change from a first power state to a second power statewhen a cover of the inhaler is moved expose a mouthpiece of the inhaler,wherein the second power state is characterized by a power consumptionthat is greater than the first power state
 38. The monitoring module ofclaim 37, wherein the first power state is an off state or a sleepstate, and the second power state is an on state.
 39. The monitoringmodule of claim 37, wherein the sensor comprises amicroelectromechanical system (MEMS) pressure sensor or ananoelectromechanical system (NEMS) pressure sensor.
 40. The monitoringmodule of claim 37, further comprising a light emitting diode (LED),wherein the processor is configured to change a color of the LED orflash the LED upon the monitoring module changing from the first powerstate to the second power state.